Research Proposal: Heart disease is the number one cause of death in people over age 65 and 84% of deaths caused by heart disease occur in the elderly population. Many of these deaths could be prevented if therapeutic strategies existed for stimulating cardiomyocyte proliferation and cardiac regeneration. As a prerequisite, the molecular pathways that regulate embryonic cardiomyocyte proliferation and the molecular barriers to proliferation in aging cardiomyocytes must be elucidated. Recent data suggest that a helicase protein, Reptin, plays a fundamental role in regulating cardiomyocyte proliferation since an activating mutation in zebrafish Reptin (called liebeskummer) causes embryonic myocardial hyperplasia. The specific aims of this proposal are designed to elucidate the mechanism by which Reptin regulates cardiomyocyte proliferation. The unique experimental approach relies on several reagents developed by the candidate and the liebeskummer mutant. Specific Aim I addresses whether Reptin is necessary for cardiomyocyte proliferation by developing and analyzing transgenic zebrafish that overexpress a dominant negative inhibitor of Reptin specifically in embryonic cardiomyocytes. Specific Aim II tests whether interactions between Reptin and the transcription factors beta-catenin and c-Myc occur in zebrafish heart and if so, whether the interactions are necessary for Reptin's regulatory role in cardiomyocyte proliferation. Experiments in Specific Aim III will identify downstream targets of Reptin by analyzing differential gene expression between wild-type and liebeskummer hearts. Together the proposed experiments will help elucidate Reptin's role in the regulator of cardiomyocyte proliferation and identify novel drug targets for stimulating cardiomyocyte proliferation and cardiac regeneration in the aging population. The candidate: The candidate, C. Geoffrey Burns Ph.D., is a fellow at Massachusetts General Hospital (MGH) in the Cardiovascular Research Center, a preeminent research institute devoted to understanding cardiovascular development, physiology, and aging. The MGH Department of Cardiology has committed numerous resources to Dr. Burns during the award period. Dr. Burns will receive primary guidance from Drs. Calum MacRae and Anthony Rosenzweig, who together have 25 years experience in cardiovascular research and track records as successful mentors. Dr. Burns has also assembled a Scientific Advisory Committee that includes two cardiovascular aging experts (Dr. Ken Minaker and Dr. Roger Hajjar) and an accomplished zebrafish developmental geneticist (Dr. lain Drummond). Dr. Burns will supplement experiential learning with relevant lab meetings, journal clubs, seminars, scientific meetings, and didactic learning the biology of aging. Ultimately, this award will aid Dr. Burns in achieving his long-term goals of becoming an independent investigator in the field of cardiac regeneration and expert in cardiovascular aging.